Atherosclerosis

Abstract

Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease's aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.

Figures

Figure 1

Structure of a normal large artery. A large artery consists of three morphologically distinct layers. The intima, the innermost layer, is bounded by a monolayer of endothelial cells on the luminal side and a sheet of elastic fibres, the internal elastic lamina, on the peripheral side. The normal intima is a very thin region (size exaggerated in this figure) and consists of extracellular connective tissue matrix, primarily proteoglycans and collagen. The media, the middle layer, consists of SMCs. The adventitia, the outer layer, consists of connective tissues with interspersed fibroblasts and SMCs.

Figure 2

Stages in the development of atherosclerotic plaques. a, In the first stages, lipoprotein is trapped in the subendothelial matrix. The freeze-etch electron micrograph shows the accumulation of 23-nm LDL particles (circled) in the matrix of a rabbit atrial-ventricular valve following incubation with LDL (inset). An endothelial cell at lower left shows the plasma membrane (MEMB) and cytoplasma (CYTO). Magnification ×141,372; scale bar, 0.1 μm. b, Lipoprotein aggregation is seen in this freeze-etch electron micrograph of rabbit intima following administration of a bolus of LDL. The aggregated particles are surrounded by matrix and collagen fibrils (asterisk). Magnification ×52,876; scale bar, 0.2 μm. c, Monocyte transmigration. The thin-section electron micrograph of a cross-section of the aorta of a 9-week-old apoE-deficient mouse shows a monocyte (arrow) moving between two endothelial cells (arrowheads) to enter the intima (int). The asterisk denotes a cluster of lipid underneath the endothelial cell. Magnification ×10,078; scale bar, 0.5 μm. d, Foam-cell formation. Freeze-etch electron micrograph of the cytoplasm of a macrophage foam cell in the intima of a rabbit fed a high-fat diet for two weeks. Large lipid droplets with the onion skin configuration typical of cholesterol esters (ce) as well as other lipid-filled compartments (arrows) can be recognized. Some compartments contain large aggregated LDL particles (asterisk) resembling those in b. Magnification ×21,542; scale bar, 0.5 μm. e, Fibrous lesion. Light micrograph (×400) of a section of an advanced human coronary atherosclerotic lesion that has been immunostained for the macrophage-specific antigen EMB-11 (red). A, adventitia; I, intima; IEL, internal elastic lamina; M, media. Photographs courtesy of A. Mottino, J. Frank and T. Drake, UCLA.

Figure 3

Lesion initiation. Sites of lesion predilection are determined in part by haemodynamic forces acting on endothelial cells. These influence the permeability of the endothelial barrier and expression of endothelial cell (EC) genes such as that for nitric oxide synthase (NOS). An important initiating event is the retention of LDL and other apolipoprotein B (apoB)-containing lipoproteins as a result of interaction with matrix components. The LDL undergoes oxidative modification as a result of interaction with reactive oxygen species (ROS) including products of 12/15 lipoxygenase (12-LO) such as HPETE. Oxidation of LDL is inhibited by HDL, which contains the antioxidant protein serum paraoxonase (PON1).

Figure 4

Inflammation. Minimally oxidized LDL stimulates the overlying endothelial cells to produce adhesion molecules, chemotactic proteins such as monocyte chemotactic protein-1 (MCP-1), and growth factors such as macrophage colony-stimulating factor (M-CSF), resulting in the recruitment of monocytes to the vessel wall. Oxidized LDL has other effects, such as inhibiting the production of NO, an important mediator of vasodilation and expression of endothelial leukocyte adhesion molecules (ELAMs). Among endothelial cell adhesion molecules likely to be important in the recruitment of leukocytes are ICAM-1, P-selectin, E-selectin, PCAM-1 and VCAM-1. Important adhesion molecules on monocytes include β2 integrin, VLA-4, and PCAM-1. Advanced glycosylation endproducts (AGEs) are formed in diabetes and these promote inflammation via specific receptors on endothelial cells.

Figure 5

Foam-cell formation. Highly oxidized aggregated LDL is formed in the vessel as a result of the action of reactive oxygen species (ROS) and the enzymes sphingomyelinase (SMase), secretory phospholipase 2 (sPLA2), other lipases, and myeloperoxidase (MPO). The oxidized aggregated LDL is recognized by macrophage scavenger receptors such as SR-A, CD36 and CD68. Scavenger receptor expression is mediated by cytokines such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Foam cells secrete apolipoprotein E (apoE), which may facilitate removal of excess cellular cholesterol. The death of foam cells leaves behind a growing mass of extracellular lipids and other cell debris.

Figure 6

Formation of fibrous plaques. A number of risk factors, including elevated levels of homocysteine and angiotensin II (produced through the action of angiotensin-converting enzyme, ACE), stimulate the migration or proliferation of SMCs. Oestrogens exert beneficial effects on plasma lipoprotein levels and they also stimulate production of NO and prostacyclin by endothelial cells. The interaction of CD40 and CD40 ligand (CD40L) stimulates T lymphocytes (T cells) and macrophages to express cytokines such as IFN-γ that can influence inflammation, SMC growth and matrix accumulation. The intimal SMCs secrete extracellular matrix and give rise to a fibrous cap.

Figure 7

Complex lesions and thrombosis. Vulnerable plaques with thin fibrous caps result from degradation of matrix by various proteinases such as collagenases, gelatinases, stromolysin and cathepsins and by inhibition of matrix secretion. Among various factors that may destabilize plaques and promote thrombosis are infection, which may have systemic effects such as induction of acute phase proteins and local effects such as increased expression of tissue factor and decreased expression of plasminogen activator (PA). The calcification of lesions appears to be an active, regulated process involving the secretion by pericyte-like cells in the intima of a scaffold for calcium phosphate deposition. The formation of a thrombus, consisting of adherent platelets and fibrin crosslinks, usually results from plaque rupture, exposing tissue factor in the necrotic core.